This research is a study of the design and synthesis of agents useful primarily in the treatment of cancer. The approach used is to study the chemical and physical properties of the metabolic sequence that may be one of the controlling or limiting processes in the synthesis of deoxyribonucleic acid and ultimately cell division. The sequence is the reductive methylation of deoxyuridine-5'-phosphate catalyzed by the enzyme thymidylate synthetase. The research objective of this problem is a continuing study of the synthesis and in vitro testing of potential thymidylate synthetase inhibitors. Specifically the effective binding characteristics of the cofactor N5N10-Methylene- tetrahydrofolic acid, for thymidylate synthetase and dihydrofolate reductase enzyme will be examined. In this manner and by application of the chemical mechanism of the reaction and the physical properties directing enzyme-substrate or inhibitor affinity the nature of the groups important to binding can be defined and by design, attempts can thereby be made for specificity of action. Samples will also be submitted to CCNSC for testing. Bibliographic references: Warren J. Woodford, Barbara A. Swartz, Conrad J. Pillar, Arieh Kampf, and Mathias P. Mertes, Synthesis of the alpha and beta Anomers of 1-(2-Deoxy-D-ribofluranosyl)-4-pyridone, J. Med. Chem., 17, 1027 (1974); J. Hes and M.P. Mertes, Di-(2-t- Butylphenyl)-phosphorochloridate: A New Selective Phosphorylating Agent, J. Org. Chem., 39,3767 (1974).